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Intestinal CD4(+) T cells are essential mediators of immune homeostasis and inflammation. Multiple subsets of CD4(+) T cells have been described in the intestine, which represents an important site for the generation and regulation of cells involved in immune responses both within and outside of the gastrointestinal tract. Recent advances have furthered our understanding of the biology of such cells in the intestine. Appreciation of the functional roles for effector and regulatory populations in health and disease has revealed potential translational targets for the treatment of intestinal diseases, including inflammatory bowel disease. Furthermore, the role of dietary and microbiota-derived factors in shaping the intestinal CD4(+) T-cell compartment is becoming increasingly understood. Here, we review recent advances in understanding the multifaceted roles of CD4(+) T cells in intestinal immunity., (© 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)

Purpose of Review: To demonstrate how dysbiosis of the human microbiome can drive autoimmune disease., Recent Findings: Humans are superorganisms. The human body harbors an extensive microbiome, which has been shown to differ in patients with autoimmune diagnoses. Intracellular microbes slow innate immune defenses by dysregulating the vitamin D nuclear receptor, allowing pathogens to accumulate in tissue and blood. Molecular mimicry between pathogen and host causes further dysfunction by interfering with human protein interactions. Autoantibodies may well be created in response to pathogens., Summary: The catastrophic failure of human metabolism observed in autoimmune disease results from a common underlying pathogenesis - the successive accumulation of pathogens into the microbiome over time, and the ability of such pathogens to dysregulate gene transcription, translation, and human metabolic processes. Autoimmune diseases are more likely passed in families because of the inheritance of a familial microbiome, rather than Mendelian inheritance of genetic abnormalities. We can stimulate innate immune defenses and allow patients to target pathogens, but cell death results in immunopathology.

The intestinal microbiota plays an important role in the development of post-natal gastrointestinal functions of the host. Recent advances in our capability to identify microbes and their function offer exciting opportunities to evaluate the complex cross talk between microbiota, intestinal barrier, immune system and the gut-brain axis. This review summarizes these interactions in the early colonization of gastrointestinal tract with a major focus on the role of intestinal microbiota in the pathogenesis of feeding intolerance in preterm newborn. The potential benefit of early probiotic supplementation opens new perspectives in case of altered intestinal colonization at birth as preventive and therapeutic agents.

The intestinal microbiota has a critical role in immune system and metabolic homeostasis, but it must be tolerated by the host to avoid inflammatory responses that can damage the epithelial barrier separating the host from the luminal contents. Breakdown of this regulation and the resulting inappropriate immune response to commensals are thought to lead to the development of inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. We proposed that the intestinal immune system is instructed by the microbiota to limit responses to luminal antigens. Here we demonstrate in mice that, at steady state, the microbiota inhibits the transport of both commensal and pathogenic bacteria from the lumen to a key immune inductive site, the mesenteric lymph nodes (MLNs). However, in the absence of Myd88 or under conditions of antibiotic-induced dysbiosis, non-invasive bacteria were trafficked to the MLNs in a CCR7-dependent manner, and induced both T-cell responses and IgA production. Trafficking was carried out by CX(3)CR1(hi) mononuclear phagocytes, an intestinal-cell population previously reported to be non-migratory. These findings define a central role for commensals in regulating the migration to the MLNs of CX(3)CR1(hi) mononuclear phagocytes endowed with the ability to capture luminal bacteria, thereby compartmentalizing the intestinal immune response to avoid inflammation.

Recent studies analysing immunogenetics and immune mechanisms controlling susceptibility to chronic bacterial infection in bronchiectasis implicate dysregulated immunity in conjunction with chronic bacterial infection. Bronchiectasis is a structural pathological end-point with many causes and disease associations. In about half of cases it is termed idiopathic, because it is of unknown aetiology. Bronchiectasis is proposed to result from a 'vicious cycle' of chronic bacterial infection and dysregulated inflammation. Paradoxically, both immune deficiency and excess immunity, either in the form of autoimmunity or excessive inflammatory activation, can predispose to disease. It appears to be a part of the spectrum of inflammatory, autoimmune and atopic conditions that have increased in prevalence through the 20th century, attributed variously to the hygiene hypothesis or the 'missing microbiota'. Immunogenetic studies showing a strong association with human leucocyte antigen (HLA)-Cw*03 and HLA-C group 1 homozygosity and combinational analysis of HLA-C and killer immunoglobulin-like receptors (KIR) genes suggests a shift towards activation of natural killer (NK) cells leading to lung damage. The association with HLA-DR1, DQ5 implicates a role for CD4 T cells, possibly operating through influence on susceptibility to specific pathogens. We hypothesize that disruption of the lung microbial ecosystem, by infection, inflammation and/or antibiotic therapy, creates a disturbed, simplified, microbial community ('disrupted microbiota') with downstream consequences for immune function. These events, acting with excessive NK cell activation, create a highly inflammatory lung environment that, in turn, permits the further establishment and maintenance of chronic infection dominated by microbial pathogens. This review discusses the implication of these concepts for the development of therapeutic interventions., (© 2012 British Society for Immunology.)

Objective: Here, we determine how formula feeding impacts the gut microbiota and host transcriptome., Background: Formula-fed (FF) infants are at risk for diseases that involve complex interactions between microbes and host immune elements such as necrotizing enterocolitis. The aims of this study were to simultaneously examine the microbiota and host transcriptional profiles of FF and maternal-fed (MF) mice to evaluate how diet impacts gut colonization and host genes., Methods: After 72 hours of FF or MF, colonic tissue was collected. 16S ribosomal RNA was sequenced with Roche GS-FLX (Genome Sequencer-FLX) pyrosequencing. Operational taxonomical unit clustering, diversity analysis, and principal coordinate analysis (PCA) were performed. Complementary DNA libraries were sequenced by Solexa. Reads were annotated by BLAST (Basic Local Alignment Search Tool) search against mouse RNA database [National Center for Biotechnology Information (NCBI) build-37] and functionally classified using the KOG (Eukaryotic Orthologous Groups) database (NCBI)., Results: Firmicutes (P < 0.001) was the dominant phylum in MF pups, whereas Proteobacteria (P < 0.001) and Bacteroidetes (P < 0.05) were dominant in FF mice. On the genus level, FF mice had increased Serratia (P < 0.001) and Lactococcus (P < 0.05) whereas MF mice had increased Lactobacillus (P < 0.001). PCA confirmed clustering by diet. Solexa sequencing demonstrated different (P < 0.05) messenger RNA transcript levels in 148 genes. Heme oxygenase 1 (P < 0.01), an oxidative stress marker, was increased 25-fold in FF mice. In addition, decreased vinculin (P < 0.05), a cytoskeletal protein associated with adherens junctions in FF pups suggested impaired gut structural integrity. Diet also impacted immune regulation, cell cycle control/gene expression, cell motility, and vascular function genes., Conclusions: FF shifted gut microbiota and structural integrity, oxidative stress, and immune function genes, presumably increasing vulnerability to disease in FF mice. Interrogation of microbial and host gene expression in FF neonates may offer new insight on how diet affects disease pathogenesis.

Significant advances have been made in our understanding of the host defense against microbial infections taking place at frontier epithelia of Drosophila flies. Immune deficiency (IMD), the major NF-κB immune response pathway induced in these epithelia, displays remarkable adaptations in its activation and regulation in the respiratory and digestive tract. The host defense against ingested pathogens is not limited to resistance, that is, the immune response. It also involves resilience, the capacity of the host to endure and repair damages inflicted by pathogens or the host's own immune response. For instance, enterocytes damaged by pathogens, the microbiota of aging flies, or host-derived reactive oxygen species (ROS), are replaced under the control of multiple pathways by the compensatory proliferation of intestinal stem cells (ISCs)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Alterations in the composition of commensal bacterial communities are associated with enhanced susceptibility to multiple inflammatory, allergic, metabolic and infectious diseases in humans. In the context of infection, commensal bacteria-derived signals can influence the host immune response to invasive pathogens by acting as an adjuvant to boost the immune response to infection or by providing tonic stimulation to induce basal expression of factors required for host defense. Conversely, some pathogens have evolved mechanisms that can utilize commensal bacteria to establish a replicative advantage within the host. Thus, examining the dynamic relationship that exists between the mammalian host, commensal bacteria and invasive pathogens can provide insights into the etiology of pathogenesis from an infection., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Intestinal epithelial cells (IECs) are one of a few cell types in the body with constitutive surface expression of natural killer group 2 member D (NKG2D) ligands, although the magnitude of ligand expression by IECs varies. Here, we investigated whether the gut microbiota regulates the NKG2D ligand expression on small IECs. Germ-free and ampicillin-treated mice were shown to have a significant increase in NKG2D ligand expression. Interestingly, vancomycin treatment, which propagated the bacterium Akkermansia muciniphila and reduced the level of IFN-γ and IL-15 in the intestine, decreased the NKG2D ligand expression on IECs. In addition, a similar increase in A. muciniphila and a decreased NKG2D ligand expression was seen after feeding with dietary xylooligosaccharides. A pronounced increase in NKG2D ligand expression was furthermore observed in IL-10-deficient mice. In summary, our results suggest that the constitutive levels of NKG2D ligand expression on IECs are regulated by microbial signaling in the gut and further disfavor the intuitive notion that IEC NKG2D ligand expression is caused by low-grade immune reaction against commensal bacteria. It is more likely that constitutively high IEC NKG2D ligand expression is kept in check by an intestinal regulatory immune milieu induced by members of the gut microbiota, for example A. muciniphila., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The importance of our inner microbial communities for proper immune responses against invading pathogens is now well accepted, but the mechanisms underlying this protection are largely unknown. In this study, we used Caenorhabditis elegans to investigate such mechanisms. Since very little is known about the microbes interacting with C. elegans in its natural environment, we began by taking the first steps to characterize the C. elegans microbiota. We established a natural-like environment in which initially germfree, wild-type larvae were grown on enriched soil. Bacterial members of the adult C. elegans microbiota were isolated by culture and identified using 16S rRNA gene sequencing. Using pure cultures of bacterial isolates as food, we identified two, Bacillus megaterium and Pseudomonas mendocina, that enhanced resistance to a subsequent infection with the Gram-negative pathogen Pseudomonas aeruginosa. Whereas protection by B. megaterium was linked to impaired egg laying, corresponding to a known trade-off between fecundity and resistance, the mechanism underlying protection conferred by P. mendocina depended on weak induction of immune genes regulated by the p38 MAPK pathway. Disruption of the p38 ortholog, pmk-1, abolished protection. P. mendocina enhanced resistance to P. aeruginosa but not to the Gram-positive pathogen Enterococcus faecalis. Furthermore, protection from P. aeruginosa was similarly induced by a P. aeruginosa gacA mutant with attenuated virulence but not by a different C. elegans-associated Pseudomonas sp. isolate. Our results support a pivotal role for the conserved p38 pathway in microbiota-initiated immune protection and suggest that similarity between microbiota members and pathogens may play a role in such protection.

Appropriate control of immune responses is a critical determinant of health. Here, we show that choline acetyltransferase (ChAT) is expressed and ACh is produced by B cells and other immune cells that have an impact on innate immunity. ChAT expression occurs in mucosal-associated lymph tissue, subsequent to microbial colonization, and is reduced by antibiotic treatment. MyD88-dependent Toll-like receptor up-regulates ChAT in a transient manner. Unlike the previously described CD4(+) T-cell population that is stimulated by norepinephrine to release ACh, ChAT(+) B cells release ACh after stimulation with sulfated cholecystokinin but not norepinephrine. ACh-producing B-cells reduce peritoneal neutrophil recruitment during sterile endotoxemia independent of the vagus nerve, without affecting innate immune cell activation. Endothelial cells treated with ACh in vitro reduced endothelial cell adhesion molecule expression in a muscarinic receptor-dependent manner. Despite this ability, ChAT(+) B cells were unable to suppress effector T-cell function in vivo. Therefore, ACh produced by lymphocytes has specific functions, with ChAT(+) B cells controlling the local recruitment of neutrophils.

Background: Commensal microbiota play a critical role in maintaining oral tolerance. The effect of food allergy on the gut microbial ecology remains unknown., Objective: We sought to establish the composition of the gut microbiota in experimental food allergy and its role in disease pathogenesis., Methods: Food allergy-prone mice with a gain-of-function mutation in the IL-4 receptor α chain (Il4raF709) and wild-type (WT) control animals were subjected to oral sensitization with chicken egg ovalbumin (OVA). Enforced tolerance was achieved by using allergen-specific regulatory T (Treg) cells. Community structure analysis of gut microbiota was performed by using a high-density 16S rDNA oligonucleotide microarrays (PhyloChip) and massively parallel pyrosequencing of 16S rDNA amplicons., Results: OVA-sensitized Il4raF709 mice exhibited a specific microbiota signature characterized by coordinate changes in the abundance of taxa of several bacterial families, including the Lachnospiraceae, Lactobacillaceae, Rikenellaceae, and Porphyromonadaceae. This signature was not shared by similarly sensitized WT mice, which did not exhibit an OVA-induced allergic response. Treatment of OVA-sensitized Il4raF709 mice with OVA-specific Treg cells led to a distinct tolerance-associated signature coincident with the suppression of the allergic response. The microbiota of allergen-sensitized Il4raF709 mice differentially promoted OVA-specific IgE responses and anaphylaxis when reconstituted in WT germ-free mice., Conclusion: Mice with food allergy exhibit a specific gut microbiota signature capable of transmitting disease susceptibility and subject to reprogramming by enforced tolerance. Disease-associated microbiota may thus play a pathogenic role in food allergy., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Colonization of the gastrointestinal (GI) tract is initiated during birth and continually seeded from the individual's environment. Gastrointestinal microorganisms play a central role in developing and modulating host immune responses and have been the subject of investigation over the last decades. Animal studies have demonstrated the impact of GI tract microbiota on local gastrointestinal immune responses; however, the full spectrum of action of early gastrointestinal tract stimulation and subsequent modulation of systemic immune responses is poorly understood. This study explored the utility of an oral microbial inoculum as a therapeutic tool to affect porcine systemic immune responses. For this study a litter of 12 pigs was split into two groups. One group of pigs was inoculated with a non-pathogenic oral inoculum (modulated), while another group (control) was not. DNA extracted from nasal swabs and fecal samples collected throughout the study was sequenced to determine the effects of the oral inoculation on GI and respiratory microbial communities. The effects of GI microbial modulation on systemic immune responses were evaluated by experimentally infecting with the pathogen Mycoplasma hyopneumoniae. Coughing levels, pathology, toll-like receptors 2 and 6, and cytokine production were measured throughout the study. Sequencing results show a successful modulation of the GI and respiratory microbiomes through oral inoculation. Delayed type hypersensitivity responses were stronger (p = 0.07), and the average coughing levels and respiratory TNF-α variance were significantly lower in the modulated group (p<0.0001 and p = 0.0153, respectively). The M. hyopneumoniae infection study showed beneficial effects of the oral inoculum on systemic immune responses including antibody production, severity of infection and cytokine levels. These results suggest that an oral microbial inoculation can be used to modulate microbial communities, as well as have a beneficial effect on systemic immune responses as demonstrated with M. hyopneumoniae infection.

Periodontal diseases reflect a tissue destructive process of the hard and soft tissues of the periodontium that are initiated by the accumulation of multispecies bacterial biofilms in the subgingival sulcus. This accumulation, in both quantity and quality of bacteria, results in a chronic immunoinflammatory response of the host to control this noxious challenge, leading to collateral damage of the tissues. As knowledge of the characteristics of the host-bacterial interactions in the oral cavity has expanded, new knowledge has become available on the complexity of the microbial challenge and the repertoire of host responses to this challenge. Recent results from the Human Microbiome Project continue to extend the array of taxa, genera, and species of bacteria that inhabit the multiple niches in the oral cavity; however, there is rather sparse information regarding variations in how host cells discriminate commensal from pathogenic species, as well as how the host response is affected by the three-dimensional architecture and interbacterial interactions that occur in the oral biofilms. This review provides some insights into these processes by including existing literature on the biology of nonoral bacterial biofilms, and the more recent literature just beginning to document how the oral cavity responds to multispecies biofilms., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Purpose of Review: This review focuses on recent advances and novel insights into the mechanistic events that may link commensal microbiota and host innate immunity in the pathophysiology of intestinal inflammation and neoplasia. Unanswered questions are discussed and future perspectives in the field are highlighted., Recent Findings: Commensal microbiota, host innate immunity, and genetics form a multidimensional network that controls homeostasis of the mucosal barrier in the intestine. Large-scale sequencing projects have begun to catalog the healthy human microbiome. Converging evidence suggests that alterations in the regulation of the complex host environment [e.g., dysbiosis and overgrowth of select commensal bacterial species, dietary factors, copresence of facultative pathogens (including viruses), and changes in mucus characteristics] may trigger aberrant innate immune signaling, thereby contributing to the development of intestinal inflammation and associated colon cancer in the susceptible individual. Genetically determined innate immune malfunction may create an inflammatory environment that promotes tumor progression (such as the TLR4-D299G mutation)., Summary: The next challenging steps to be taken are to decipher changes in the human microbiome (and virome) during well defined diseased states, and relate them to intestinal mucosal immune functions and host genotypes.

Staphylococcus aureus is a common human pathogen, which is regularly part of the normal microflora found in the nose and skin. It represents a significant threat to human health, not in the least because of its capability to produce exotoxins, which have superantigenic properties. These exotoxins, in particular the staphylococcal enterotoxins (SEs), are known to be involved in the modulation and aggravation of airway inflammation. Indeed, recent studies show an important impact of SEs on the natural course of allergic rhinitis, nasal polyposis, asthma and COPD. This review outlines the current knowledge on the influence of SEs on airway inflammation. We highlight, in particular, the recent evidence on their role in asthma., (Copyright © 2013 S. Karger AG, Basel.)

Purpose of Review: Nod-like receptors (NLRs) are intracellular innate immune sensors of microbes and danger signals that control multiple aspects of inflammatory responses. We review the evidence that highlights the critical importance of NLRs in the host response to intestinal pathogens. Moreover, we discuss the potential roles played by NLRs in the dynamic control of the intestinal microbiota and how commensal microorganisms may affect host susceptibility to enteric bacterial pathogens through interactions with NLRs as well as with invading pathogens., Recent Findings: Recent studies targeting the intestinal microbiota in the context of NLR deficiencies suggest inherent alterations in bacterial density or abundance may underlie the development of inflammatory diseases. As commensal microorganisms may also affect host susceptibility to enteric bacterial pathogens, NLRs might promote intestinal innate immune defense through mechanisms more complex than previously anticipated., Summary: The inclusion of the intestinal microbiota as a critical parameter in innate immunity represents an exciting new dimension for understanding NLR functioning and the clinical implications for human health.

Purpose of Review: Bacterial colonization of the infant intestinal tract begins at birth. We are at the forefront of understanding complex relationships between bacteria and multiple parameters of health of the developing infant. Moreover, the establishment of the microbiome in the critical neonatal period is potentially foundational for lifelong health and disease susceptibility. Recent studies utilizing state-of-the-art culture-independent technologies have begun to increase our knowledge about the gut microbiome in infancy, the impact of multiple exposures, and its effects on immune response and clinical outcomes such as allergy and infection., Recent Findings: Postnatal exposures play a central role in the complex interactions between the nearly blank canvas of the neonatal intestine, whereas genetic factors do not appear to be a major factor. Infant microbial colonization is affected by delivery mode, dietary exposures, antibiotic exposure, and environmental toxicants. Successive microbiome acquisition in infancy is likely a determinant of early immune programming, subsequent infection, and allergy risk., Summary: The novel investigation of the neonatal microbiome is beginning to unearth substantial information, with a focus on immune programming that coevolves with the developing microbiome early in life. Several exposures common to neonatal and infant populations could exert pressure on the development of the microbiome and major diseases including allergy and infection in large populations.

Gut microbiota constitute a highly complex ecosystem that interacts with the host and profoundly affects gastrointestinal and systemic immunologic functions. Specific microbial patterns are associated with healthy children and adults, and these patterns are greatly related to the early acquisition of microbes by the newborn and the development of gut microbial communities in the perinatal period. Although direct causation must be firmly established and mechanisms fully elucidated, strong and increasing evidence shows that the early acquisition, development, and maintenance of specific bacterial populations are critical to human health, and a better understanding of these offers great opportunities for intervention., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Gut microbiota composition can discriminate between allergic and healthy children, and the distinction may precede clinical manifestations of disease. The mother provides the first inoculum of bacteria, which influences the risk of becoming allergic later in life. Bifidobacterium species are major determinants of disease risk. Specific probiotics may modulate early microbial colonization, which represents the first intervention target in allergic disease, together with their ability to reverse the increased intestinal permeability characteristic of children with atopic eczema and food allergy. Probiotics also enhance gut-specific IgA responses, which are frequently defective in children with food allergy. In addition, probiotics have the potential to alleviate allergic inflammation locally and systemically., (Copyright © 2012. Published by Elsevier Inc.)

In the US and other developed countries, food allergy is a growing epidemic in pediatric populations with a substantial impact on health-related quality of life. As such, there are great efforts underway to unravel the mechanisms of oral mucosal tolerance and to better define the factors related to host and allergen exposure that contribute to the aberrant immune response leading to sensitization and clinical food allergy. Although more research is needed to eventually develop targeted treatment and prevention strategies, this review highlights our current understanding of the pathogenesis of IgE-mediated food allergy.

Carcinoembryonic antigen cell adhesion molecule like I (CEACAM1) is expressed on activated T cells and signals through either a long (L) cytoplasmic tail containing immune receptor tyrosine based inhibitory motifs, which provide inhibitory function, or a short (S) cytoplasmic tail with an unknown role. Previous studies on peripheral T cells show that CEACAM1-L isoforms predominate with little to no detectable CEACAM1-S isoforms in mouse and human. We show here that this was not the case in tissue resident T cells of intestines and gut associated lymphoid tissues, which demonstrated predominant expression of CEACAM1-S isoforms relative to CEACAM1-L isoforms in human and mouse. This tissue resident predominance of CEACAM1-S expression was determined by the intestinal environment where it served a stimulatory function leading to the regulation of T cell subsets associated with the generation of secretory IgA immunity, the regulation of mucosal commensalism, and defense of the barrier against enteropathogens., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose of Review: The prevalence of allergic diseases continues to rise globally in developed countries. Since the initial proposal of the hygiene hypothesis, there has been increasing evidence to suggest that the intestinal microbiota, particularly during early infancy, plays a critical role in regulating immune responses associated with the development of atopy. This review evaluates the key epidemiologic and mechanistic data published to date., Recent Findings: Epidemiological data have provided the framework for animal studies investigating the importance of gut commensals in allergy development. These studies provide new insights about the microbial regulation of mucosal immune responses inside and outside the gut, and how these effects may drive allergic inflammation in susceptible individuals. Specific immune cells have been identified as mediators of these microbiota-regulated allergic responses., Summary: In the last year, technological advances have provided us with a better understanding of the gut microbiome in healthy and allergic individuals. Recent studies have identified the associations between particular gut microbes and different disease phenotypes, as well as identified immune cells and their mediators involved in allergy development. This research has provided a number of host and microbe targets that may be used to develop novel therapies suitable for the treatment or prevention of allergic diseases.

This article discusses the role that immunity plays in the risk of diarrhoea and the potential role for probiotics in the management of acute infectious diarrhoea in older people, including antibiotic-associated diarrhoea and Clostridium difficile-associated diarrhoea.

Innate and adaptive mucosal defense mechanisms ensure a homeostatic relationship with the large and complex mutualistic gut microbiota. Dimeric IgA and pentameric IgM are transported across the intestinal epithelium via the epithelial polymeric Ig receptor (pIgR) and provide a significant portion of the first line of natural or adaptive antibody-mediated immune defense of the intestinal mucosa. We found that colonic epithelial cells from pIgR KO mice differentially expressed (more than twofold change) more than 200 genes compared with cells from WT mice, and upregulated the expression of antimicrobial peptides in a commensal-dependent manner. Detailed profiling of microbial communities based on 16S rRNA genes revealed differences in the commensal microbiota between pIgR KO and WT mice. Furthermore, we found that pIgR KO mice showed increased susceptibility to dextran sulfate sodium-induced colitis, and that this was driven by their conventional intestinal microbiota. Thus, in the absence of pIgR, the stability of the commensal microbiota is disturbed, gut homeostasis is compromised, and the outcome of colitis is significantly worsened., (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Alterations in intestinal microflora have been linked to the development of allergic disease. Recent studies suggest that healthy infant immune development may depend on the establishment of a diverse gut microbiota rather than the presence or absence of specific microbial strains., Objectives: We investigated the relationship between diversity of gut microbiota in the early postnatal period and subsequent development of eczema and atopy in the first year of life., Methods: Fecal samples were collected 1 wk after birth from 98 infants at high risk of allergic disease, who were followed prospectively to age 12 months. Fecal microbial diversity was assessed by terminal restriction fragment length polymorphism (T-RFLP) using restriction enzymes Sau96I and AluI, with a greater number of peaks representing greater diversity of bacterial communities., Results: Microbial diversity at day 7 was significantly lower in infants with eczema at age 12 months as compared to infants without eczema (AluI mean number of peaks 13.1 vs. 15.5, p = 0.003, 95% CI for difference in means -3.9, -0.8; Sau96I 14.7 vs. 17.2, p = 0.03, 95% CI -4.9, -0.3). No differences were observed for atopic compared to non-atopic infants, or infants with two allergic parents compared to those with one or no allergic parent., Conclusions: A more diverse intestinal microbiota in the first week of life is associated with a reduced risk of subsequent eczema in infants at increased risk of allergic disease. Interventions that enhance microbial diversity in early life may provide an effective means for the prevention of eczema in high-risk infants., (© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd.)

Hashimoto's thyroiditis is an organ-specific autoimmune disease in which both genetic predisposition and environmental factors serve as the trigger of the disease. A growing body of evidence suggests involvement of viral infection in the development of Hashimoto's thyroiditis. However, not only pathogenic microorganisms but also non-pathogenic commensal microorganisms induce proinflammatory or regulatory immune responses within the host. In accordance, series of studies indicate a critical role of intestinal commensal microbiota in the development of autoimmune diseases including inflammatory bowel diseases, type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. In contrast, the role of the gut and indigenous microorganisms in Hashimoto's thyroiditis has received little attention. Whereas activation of innate pattern recognition receptors such as Toll-like receptors and disturbed intestinal epithelial barrier may contribute to thyroiditis development, only a few studies have addressed a link between the gut and Hashimoto's thyroiditis and provided just indirect and weak evidence for such a link. Despite this unsatisfactory situation, we here focus on the possible interaction between the gut and thyroid autoimmunity. Further studies are clearly needed to test the hypothesis that the gut commensal microflora represents an important environmental factor triggering Hashimoto's thyroiditis.

Purpose of Review: To briefly summarize some of the principles of epigenetics and assess their potential relevance for the disease pathogenesis of inflammatory bowel diseases (IBDs). To review the results of recent IBD-related epigenetic studies, discuss main challenges as well as highlight the opportunities for future research in this field., Recent Findings: Evidence is accumulating for a major role of epigenetic mechanisms in the disease pathogenesis of several immune-mediated diseases. Recent findings indicate that epigenetics may mediate some of the effects of environment, genetic predisposition and intestinal microbiota on IBD pathogenesis., Summary: Epigenetics is a rapidly expanding and hugely promising area of research. At best, it may provide a unifying molecular mechanism to explain complex immune-mediated diseases such as IBD. Future research studies must be carefully designed, performed and analysed taking into account the basic principles of epigenetics in order to ensure the true potential of this field is realized in the understanding of IBD.

Commensal bacteria are necessary for the development and maintenance of a healthy immune system. Harnessing the ability of microbiota to affect host immunity is considered an important therapeutic strategy for many mucosal and nonmucosal immune-related conditions, such as inflammatory bowel diseases (IBDs), celiac disease, metabolic syndrome, diabetes, and microbial infections. In addition to well-established immunostimulatory effects of the microbiota, the presence of individual mutualistic commensal bacteria with immunomodulatory effects has been described. These organisms are permanent members of the commensal microbiota and affect host immune homeostasis in specific ways. Identification of individual examples of such immunomodulatory commensals and understanding their mechanisms of interaction with the host will be invaluable in designing therapeutic strategies to reverse intestinal dysbiosis and recover immunological homeostasis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Maximising the ability of piglets to survive exposure to pathogens is essential to reduce early piglet mortality, an important factor in efficient commercial pig production. Mortality rates can be influenced by many factors, including early colonization by microbial commensals. Here we describe the development of an intestinal microbiota, the Bristol microbiota, for use in gnotobiotic pigs and its influence on synthesis of systemic immunoglobulins. Such a microbiota will be of value in studies of the consequences of early microbial colonization on development of the intestinal immune system and subsequent susceptibility to disease. Gnotobiotic pig studies lack a well-established intestinal microbiota. The use of the Altered Schaedler Flora (ASF), a murine intestinal microbiota, to colonize the intestines of Caesarean-derived, gnotobiotic pigs prior to gut closure, resulted in unreliable colonization with most (but not all) strains of the ASF. Subsequently, a novel, simpler porcine microbiota was developed. The novel microbiota reliably colonized the length of the intestinal tract when administered to gnotobiotic piglets. No health problems were observed, and the novel microbiota induced a systemic increase in serum immunoglobulins, in particular IgA and IgM. The Bristol microbiota will be of value for highly controlled, reproducible experiments of the consequences of early microbial colonization on susceptibility to disease in neonatal piglets, and as a biomedical model for the impact of microbial colonization on development of the intestinal mucosa and immune system in neonates., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Metabolites released by the gut microbiota may influence host metabolism and immunity. We have tested the hypothesis that inulin-type fructans (ITF), by promoting microbial production of short-chain fatty acids (SCFA), influence cancer cell proliferation outside the gut., Methods: Mice transplanted with Bcr-Abl-transfected BaF3 cells, received ITF in their drinking water. Gut microbiota was analysed by 16S rDNA polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) and qPCR. Serum Short-chain fatty acids were quantified by UHPLC-MS. Cell proliferation was evaluated in vivo, by molecular biology and histology, and in vitro., Results: Inulin-type fructans treatment reduces hepatic BaF3 cell infiltration, lessens inflammation and increases portal propionate concentration. In vitro, propionate reduces BaF3 cell growth through a cAMP level-dependent pathway. Furthermore, the activation of free fatty acid receptor 2 (FFA2), a Gi/Gq-protein-coupled receptor also known as GPR43 and that binds propionate, lessens the proliferation of BaF3 and other human cancer cell lines., Conclusion: We show for the first time that the fermentation of nutrients such as ITF into propionate can counteract malignant cell proliferation in the liver tissue. Our results support the interest of FFA2 activation as a new strategy for cancer therapeutics. This study highlights the importance of research focusing on gut microbes-host interactions for managing systemic and severe diseases such as leukaemia.

Resistance mechanisms of the innate and adaptive immune responses prevent the colonization of foreign organisms in unwanted anatomical sites and participate in tissue repair and restoration of homeostasis after damage induced either by the invasion of pathogenic microbes or by the organism's response to them. The intensity of the response is controlled and limited by positive and negative feedback circuits that aim at preventing collateral tissue damage. In this Review we will discuss the protective and pathogenic effects of host-commensal microbiota mutualism on the immune response and illustrate some examples of collateral tissue and systemic damage caused by immunity to pathogens.

As opposed to IgE mediated food allergy (IFA) which can cause fatal outcomes, non-IgE mediated FA (NFA) was initially thought to be a benign condition mediated by cellular immune responses, primarily affecting the GI mucosa. NFA children were thought to recover well upon avoidance of offending food. Although pathogenesis of NFA is still not well understood, recent studies indicate widely variable clinical manifestations of NFA. In parallel to our better appreciation of clinical features of NFA, complex regulatory mechanisms of gut immune homeostasis have become known with progress in our understanding of the gut mucosal immune system. In addition, a role of gut commensal flora on the gut immune system has also become better understood along with the effects of dietary components. Subtle changes in interactions between environmental factors (microbiota, dietary components, etc.) and the gut immune responses can affect gut immune homeostasis, which can result in undesired adverse reactions to food proteins (FPs). This review discusses recent progress in our understanding of the regulatory mechanisms of gut immune homeostasis and recently revealed widely variable clinical presentations of NFA with respect to it pathogenesis.

Th17 cells are an effector lineage of CD4 T cells that can contribute to protection against microbial pathogens and to the development of harmful autoimmune and inflammatory conditions. An increasing number of studies suggests that Th17 cells play an important protective role in mobilizing host immunity to extracellular and intracellular microbial pathogens, such as Candida and Salmonella. Furthermore, the generation of Th17 cells is heavily influenced by the normal microbial flora, highlighting the complex interplay among harmless microbes, pathogens, and host immunity in the regulation of pathogen-specific Th17 responses. In this article, we review the current understanding of microbe-induced Th17 cells in the context of infectious and inflammatory disease.

The pathogenesis of atopic dermatitis (AD) requires the orchestration of multiple immune cells that mediate inflammation and tissue remodeling in the skin. T helper cell subsets that secrete specific cytokines have a central role in regulating the inflammatory process. In this review we discuss defined roles for T helper subsets in AD, how the microbiome might impact the development and function of T helper subsets, and animal models that will be useful for testing hypotheses on the interactions of a polarized T-cell response with skin inflammation. Future studies that link these areas will provide important insight into the development of skin inflammation and AD.

Foxp3 activity is essential for the normal function of the immune system. Two types of regulatory T (T reg) cells express Foxp3, thymus-generated natural T reg (nT reg) cells, and peripherally generated adaptive T reg (iT reg) cells. These cell types have complementary functions. Until now, it has not been possible to distinguish iT reg from nT reg cells in vivo based solely on surface markers. We report here that Neuropilin 1 (Nrp1) is expressed at high levels by most nT reg cells; in contrast, mucosa-generated iT reg and other noninflammatory iT reg cells express low levels of Nrp1. We found that Nrp1 expression is under the control of TGF-β. By tracing nT reg and iT reg cells, we could establish that some tumors have a very large proportion of infiltrating iT reg cells. iT reg cells obtained from highly inflammatory environments, such as the spinal cords of mice with spontaneous autoimmune encephalomyelitis (EAE) and the lungs of mice with chronic asthma, express Nrp1. In the same animals, iT reg cells in secondary lymphoid organs remain Nrp1(low). We also determined that, in spontaneous EAE, iT reg cells help to establish a chronic phase of the disease.

The mammalian gastrointestinal tract contains a large and diverse population of commensal bacteria and is also one of the primary sites of exposure to pathogens. How the immune system perceives commensals in the context of mucosal infection is unclear. Here, we show that during a gastrointestinal infection, tolerance to commensals is lost, and microbiota-specific T cells are activated and differentiate to inflammatory effector cells. Furthermore, these T cells go on to form memory cells that are phenotypically and functionally consistent with pathogen-specific T cells. Our results suggest that during a gastrointestinal infection, the immune response to commensals parallels the immune response against pathogenic microbes and that adaptive responses against commensals are an integral component of mucosal immunity.

The emergence of the adaptive immune system in vertebrates set the stage for evolution of an advanced symbiotic relationship with the intestinal microbiota. The defining features of specificity and memory that characterize adaptive immunity have afforded vertebrates the mechanisms for efficiently tailoring immune responses to diverse types of microbes, whether to promote mutualism or host defence. These same attributes can put the host at risk of immune-mediated diseases that are increasingly linked to the intestinal microbiota. Understanding how the adaptive immune system copes with the remarkable number and diversity of microbes that colonize the digestive tract, and how the system integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise for new approaches to modulate immune networks to treat and prevent disease.

The link between the microbes in the human gut and the development of obesity, cardiovascular disease and metabolic syndromes, such as type 2 diabetes, is becoming clearer. However, because of the complexity of the microbial community, the functional connections are less well understood. Studies in both mice and humans are helping to show what effect the gut microbiota has on host metabolism by improving energy yield from food and modulating dietary or the host-derived compounds that alter host metabolic pathways. Through increased knowledge of the mechanisms involved in the interactions between the microbiota and its host, we will be in a better position to develop treatments for metabolic disease.

Intestinal epithelial cells (IECs) form a physical and immunological barrier that separates the vast gut microbiota from host tissues. MyD88-dependent Toll-like receptor signaling is a key mediator of microbial-host cross-talk. We examined the role of epithelial MyD88 expression by generating mice with an IEC-targeted deletion of the Myd88 gene (MyD88(ΔIEC)). Loss of epithelial MyD88 signaling resulted in increased numbers of mucus-associated bacteria; translocation of bacteria, including the opportunistic pathogen Klebsiella pneumoniae, to mesenteric lymph nodes; reduced transmucosal electrical resistance; impaired mucus-associated antimicrobial activity; and downregulated expression of polymeric immunoglobulin receptor (the epithelial IgA transporter), mucin-2 (the major protein of intestinal mucus), and the antimicrobial peptides RegIIIγ and Defa-rs1. We further observed significant differences in the composition of the gut microbiota between MyD88(ΔIEC) mice and wild-type littermates. These physical, immunological, and microbial defects resulted in increased susceptibility of MyD88(ΔIEC) mice to experimental colitis. We conclude that MyD88 signaling in IECs is crucial for maintenance of gut homeostasis.

Intestinal commensal bacteria induce protective and regulatory responses that maintain host-microbial mutualism. However, the contribution of tissue-resident commensals to immunity and inflammation at other barrier sites has not been addressed. We found that in mice, the skin microbiota have an autonomous role in controlling the local inflammatory milieu and tuning resident T lymphocyte function. Protective immunity to a cutaneous pathogen was found to be critically dependent on the skin microbiota but not the gut microbiota. Furthermore, skin commensals tuned the function of local T cells in a manner dependent on signaling downstream of the interleukin-1 receptor. These findings underscore the importance of the microbiota as a distinctive feature of tissue compartmentalization, and provide insight into mechanisms of immune system regulation by resident commensal niches in health and disease.